Novel benzoic acid derivatives and process for preparing the same

ABSTRACT

Benzoic acid derivatives represented by the formula (I): ##STR1## wherein R 1  represents hydrogen or lower-alkyl, R 2  and R 4  represent hydrogen, trimethylsilyl, or trimethylgermyl, R 3  represents hydrogen, lower-alkyl, trimethylsilyl, or trimethylgermyl, R 5  represents hydrogen, lower-alkyl, acetyl, or hydroxy, at least one of R 2  and R 3  being trimethylsilyl or trimethylgermyl, and R 6  means hydroxy, lower-alkoxy, or a group of the formula --NR 7  R 8 , wherein R 7  and R 8  mean hydrogen or lower-alkyl, and X represents a group of the formula --COHN--, --NHCO--, --COO--, --OCO--, --COCH═CH--, --COCH═C(OH)--, or --CH═CH--, which exhibit excellent effect as differentiation-inducing agents for neoplastic cells, especially leukemia cells, or a therapeutic agent for psoriasis or immune and inflammatory diseases, and a process for the preparation thereof, are disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel benzoic acid derivativesrepresented by the general formula (I), which have great potential asuseful medicaments, and a process for preparing the same. ##STR2## Thevariables in the formula are described in detail in the following.

2. Description of the Prior Art

In Japan Kokai 61-22046, 61-22047 and 61-76440, it was already shownthat benzoic acid derivatives represented by the general formula (II):##STR3## wherein R'₁, R'₂, R'₃, R'₄ and R'₅ are the same or different,and each represents hydrogen or middle or lower-alkyl, with the provisothat all can not be hydrogen simultaneously, and wherein two neighboringsubstituents may be combined with each other to form a cycloalkyl ringhaving 5 to 6 carbon atoms, R'₆ represents hydroxyl, lower-alkoxyl, orlower-alkylamino of the formula --NR'₇ R'₈, wherein R'₇ and R'₈ eachrepresents hydrogen or lower-alkyl, and X' represents a group of theformula: are capable of inducing the differentiation of malignant cells,especially leukemia cells, to morphologically and functionally maturecells which cannot proliferate further, and are accordinglypharmacologically valuable and useful for treatment of malignantproliferous or immune diseases such as cancer, rheumatism, or psoriasis,and in Japan Kokai 62-215581, there are also shown related compounds.The literature also shows the activity and measurement of the activityof those compounds by the differentiation of human acute promyelocyticleukemia cells (HL-60).

Such a compound, wherein R'₂, R'₃ and R'₄ each is a middle alkyl group,especially wherein one alkyl substituent is isopropyl or butyl, andwherein two alkyl substituents R'₂ and R'₃ are combined into a ringhaving 5 to 6 carbon atom, is especially effective. On the other handsuch a compound, wherein both of R'₃ and R'₄ are hydrogen, does notexhibit the desired activity. Such a compound, wherein R'₇ and R'₈ arehydrogen or methyl, and wherein R'₆ is hydroxyl or methoxy, isespecially effective. The subject of the present invention consists indiminishing the undesirable side-effects which the above-identifiedcompounds are known to possess and providing additional new compoundshaving the same therapeutic potential.

3. Summary of the Invention

It has now been found that benzoic acid derivatives represented by theformula (I): ##STR4## wherein R₁ represents hydrogen or lower-alkyl, R₂and R₄ represent hydrogen, trimethylsilyl, or trimethylgermyl, R₃represents hydrogen, lower-alkyl, trimethylsilyl, or trimethylgermyl, R₅represents hydrogen, lower-alkyl, acetyl, or hydroxy, at least one of R₂and R₃ being trimethylsilyl or trimethylgermyl, and R₆ means hydroxy,lower-alkoxy, or a group of the formula --NR₇ R₈, wherein R₇ and R₈ meanhydrogen or lower-alkyl, and X represents a group of the formula--CONH--, --NHCO--, --COO--, --OCO--, --COCH═CH--, --COCH=C(OH)--, or--CH═CH--, exhibit excellent effect as differentiation-inducing agentsfor neoplastic cells, especially leukemia cells. Further, according tothe present invention, there is also provided a process for preparationof the novel benzoic acid derivatives represented by the formula (I).

DETAILED DESCRIPTION OF THE INVENTION

By the term "lower" in formula (I) is meant a straight or branchedcarbon chain having 1-4 carbon atoms. Therefore, the lower-alkyl moietyof the lower-alkyl group encompassed by R₁, R₃, R₅, R₇ and R₈ isrepresentatively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, and tert-butyl. The lower-alkoxy moiety of the lower-alkoxygroup encompassed by R₆ is representatively methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, etc.

The compounds represented by formula (I) form salts with bases. Thisinvention includes the pharmaceutically-acceptable salts of thecompounds of formula (I) and examples of these salts are salts withalkali metals such as sodium, potassium, etc., or alkaline earth metalssuch as calcium, etc.; salts with ammonia; and salts with organic basessuch as methylamine, ethylamine, trimethylamine, triethylamine,pyridine, picoline, arginine, lysine, etc.

The novel benzoic acid derivatives represented by the formula (I) can beprepared by the following methods:

(a) a compound represented by the formula (I), wherein X represents agroup of the formula --CONH--, is prepared by condensation of afunctional derivatives such as the acid halide or ester, derived from abenzoic acid derivative represented by the formula (III): ##STR5##wherein R₁, R₂, R₃, R₄ and R₅ have the meanings described above, with ap-aminobenzoic acid or its derivative, or

(b) a compound represented by the formula (I), wherein X represents agroup of the formula --NHCO--, is prepared by condensation of an anilinederivative represented by the formula (IV): ##STR6## wherein R₁, R₂, R₃,R₄ and R₅ have the meanings described above, with a functionalderivative, such as the acid halide or ester, of terephthalic acid, or

(c) a compound represented by the formula (I), wherein X represents agroup of the formula --COO--, is prepared by condensation of afunctional derivative, such as the acid halide or ester, derived from abenzoic acid derivative represented by the formula (III), with ap-hydroxybenzoic acid or its derivative, or

(d) a compound represented by the formula (I), wherein X represents agroup of the formula --OCO--, is prepared by condensation of a phenolderivative represented by the formula (V): ##STR7## wherein R₁, R₂, R₃,R₄ and R₅ have the meanings described above, with a functionalderivative, such as the acid halide or ester, of terephthalic acid, or

(e) a compound represented by the formula (I), wherein X represents agroup of the formula --COCH═CH--, is prepared by condensation of anacetophenone derivative represented by the formula (VI): ##STR8##wherein R₁, R₂, R₃, R₄ and R₅ have the meanings described above, with aterephthalaldehydic acid or its derivative in the presence of a base, or

(f) a compound represented by the formula (I), wherein X represents agroup of the formula --COCH═C(OH)-- and R₅ represents hydroxy, isprepared by condensation of an o-hydroxyacetophenone derivativerepresented by the formula (VII): ##STR9## wherein R₁, R₂, R₃ and R₄have the meanings described above, with a terephthalic acid or itsderivative to give an ester represented by the formula (VIII): ##STR10##wherein R₁, R₂, R₃, R₄ and R₆ have the meanings described above, whichis followed by rearrangement in the presence of an alkali catalyst, or

(g) a compound represented by the formula (I), wherein X represents agroup of the formula --CH═CH--, is prepared by condensation of abenzylphosphonium salt represented by the formula (IX): ##STR11##wherein R₁, R₂, R₃, R₄ and R₅ each have the meanings described above,and Z means halogen, with a terephthalaldehydic acid or its derivativein the presence of a base and, if necessary or desirable, thethus-obtained compound is hydrolyzed using an alkali catalyst.

The compounds having a trimethylsilyl or trimethylgermyl group, whichare starting materials, can be prepared in the following manner. One wayis using the Grignard reaction with a bromobenzene derivative andtrimethylsilyl chloride or trimethylgermyl chloride, as shown in thefollowing scheme: ##STR12## Another way is using an aromaticsubstitution reaction, which utilizes the de-trimethylsilyl (or germyl)action of poly-trimethylsilyl (or germyl) benzene, as shown in thefollowing scheme: ##STR13##

Typical examples of benzoic acid derivatives embraced by the presentinvention are illustrated below.

4-(3-trimethylsilylphenylcarbamoyl)benzoic acid

4-[3,5-bis(trimethylsilyl)phenylcarbamoyl]benzoic acid

4-(3-trimethylgermylphenylcarbamoyl)benzoic acid

4-[3,5-bis(trimethylgermyl)phenylcarbamoyl]benzoic acid

4-(3-trimethylsilylphenylcarboxamido)benzoic acid

4-[3,5-bis(trimethylsilyl)phenylcarboxamido]benzoic acid

4-[3,5-bis(trimethylgermyl)phenylcarboxamido]benzoic acid

methyl 4-(3-trimethylsilylphenylcarboxy)benzoate

methyl 4-[3,5-bis(trimethylsilyl)phenylcarboxy]benzoate

methyl 4-(3-trimethylgermylphenylcarboxy)benzoate

methyl 4-[3,5-bis(trimethylgermyl)phenylcarboxy]benzoate

4-[3-(3-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoic acid

4-[3-[3,5-bis(trimethylsilyl)phenyl]-3-oxo-1-propenyl]benzoic acid

4-[3-(3-trimethylgermylphenyl)-3-oxo-1-propenyl]benzoic acid

4-[3-[3,5-bis(trimethylgermyl)phenyl]-3-oxo-1-propenyl]benzoic acid

4-[1-hydroxy-3-(2-hydroxy-4-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoicacid

4-[1-hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoicacid

4-[1-hydroxy-3-(2-hydroxy-4-trimethylgermylphenyl)-3-oxo-1-propenyl]benzoicacid

4-[1-hydroxy-3-(2-hydroxy-5-trimethylgermylphenyl)-3-oxo-1-propenyl]benzoicacid

4-[(3-trimethylsilylphenyl)ethenyl]benzoic acid

4-[[3,5-bis(trimethylsilyl)phenyl]ethenyl]benzoic acid

4-[(3-trimethylgermylphenyl)ethenyl]benzoic acid, and

4-[[3,5-bis(trimethylgermyl)phenyl]ethenyl]benzoic acid

The compounds represented by formula (I) are all capable of inducing thedifferentiation of malignant cells, especially leukemia cells,morphologically and functionally, and can therefore be used in thetreatment of tumors and cancers, leukemia, T cell malignant diseases,proliferous immune malignant dermatological diseases such as psoriasis,and immune diseases and used for the immunosuppressant in thetransplantation of organs. For the therapy of cancer such as T celllymphoma, acute promyelocytic leukemia, neuroblastoma, and carcinoma,the compounds of this invention can be used systemically, for example byinjection or oral administration, in an amount of less than 5 mg/Kg/day,preferably 0.001-1 mg/Kg/day and, for therapy of dermatological diseasessuch as psoriasis and other dermatological diseases, topically forexample as ointments containing the compound itself or a mixture withother medicaments such as a corticosteroid, anthraline, and UVtherapeutica, in an amount of 0.1-10 mg of the active compound per gramof ointment.

The test of the activities of the compounds of this invention has beenconducted by measuring the concentration required for inducing thedifferentiation of human acute promyelocytic leukemia cells (HL 60),according to the methods described in detail hereinafter.

Experimental

The compounds of this invention are tested according to established testprocedure which shows the differentiation of malignant cells, wherebythe differentiation of human acute promyelocytic leukemia cells (HL-60)and their conversion to granulocytes (myelocytes) is assayed by anobservation of the morphological changes of nuclei and by themeasurement of the degree of reduction of nitro-blue tetrazolium (NBT)which is induced by a test compound (Proc. Natl. Acad. Sci. USA 77, 29362940 (1980) with the Title: Induction of differentiation of the humanpromyelocytic leukemia cell line (HL-60) by retinoic acid). The HL-60cells are cultured in plastic flasks in RPMI 1640 medium supplementedwith 5% heat-inactivated fetal calf serum and antibiotics (penicillin Gand streptomycin). The cells (3×10⁴ /ml) are cultured with a compound ofthe present invention for 4 days. The cells are fixed and stained withWright-Giemsa to examine the morphological changes of the nuclei.

The cells treated with the compounds of the present invention aredifferentiated to mature granulocytes (myelocytes, metamyelocytes andneutrophiles), just as the cells treated with retinoic acid. Thebiochemical activity of cells treated with the compound is measured asfollows:

The cells after 5 days incubation are centrifuged and diluted with RPMI1640 medium, supplemented with 5% fetal calf serum, to provide adefinite number of the cells. To the diluted cell suspension are thenadded 200 ng/ml of 12-o-tetradodecanoylphorbol-13-acetate (TPA) and theresulting culture medium is then incubated for 20 minutes at 37 ° C. inthe presence of 0.1% of NBT. Thus, the mature differentiated cellscontaining blue-black formazan are counted by microscope, so that theratio of the cells having the ability to reduce NBT, to total cells, canbe calculated.

The cells treated with a compound of this invention show an NBTreduction activity which corresponds to the important biochemicalactivity of differentiated cells.

The results of the tests according to the above-mentioned method aresummarized in Table 1.

As a positive control for comparison, the known compounds represented bythe formula (II) and trans retinoic acid were used.

                  TABLE 1                                                         ______________________________________                                        No.  Test Compound             ED.sub.50 (M)*                                 ______________________________________                                             Present compound                                                               ##STR14##                8 × 10.sup.-8                                  ##STR15##                2 × 10.sup.-8                                  ##STR16##                3 × 10.sup.-8                                  ##STR17##                .sup. 4 × 10.sup.-10                           ##STR18##                .sup. 2 × 10.sup.-10                           ##STR19##                6 × 10.sup.-8                                 Reference compound                                                             ##STR20##                1 × 10.sup.-7                                  ##STR21##                1 × 10.sup.-6                                  ##STR22##                .sup. 4 × 10.sup.-10                     10.  retinoic acid             2 × 10.sup.-9                            ______________________________________                                         *ED.sub.50 : Effective doses which cause differentiation of 50% of the        cultured cells, M(mol/l).                                                

The results shown in Table 1 indicate that the activity of the compoundsof this invention is equal to or greater than that of known compounds ofthe formula (II) and retinoic acid. Thus, these compounds are veryuseful in the determination of promyelocytic leukemia and the diseaseswhich is accompanied by hyperkeratinization or inflammation, such aspsoriasis, which enables the selection of a proper therapeutical methodof approach.

The following References and Examples are given by way of illustrationonly and are not to be construed as limitations of this invention.

REFERENCE 1 p-Trimethylgermylacetophenone

a) 2-(4-Trimethylgermylphenyl)-2-methyl-1,3-dioxolane To a mixture of108 mg (4.44 mmol) of magnesium and 766 mg (5.00 mmol) oftrimethylgermyl chloride was added a solution of 972 mg (4.00 mmol) of2-(4-bromophenyl)-2-methyl-1,3-dioxolane in 12 ml of dry tetrahydrofuran(THF) at 40 ° C. with stirring. The mixture was refluxed for 1.5 hoursand stirred at room temperature overnight. An insoluble substance wasfiltered off and washed with ether. The filtrate and washings were mixedand evaporated. The residue was purified by column chromatography onsilica gel [eluent: petroleum ether-methylene chloride (2:1-1:2)] andrecrystallized from petroleum ether to give 524 mg of white prisms,m.p.63.5°-65° C.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.38 (9H,s), 1.66 (3H,s), 3.74-3.83(2H,m), 4.00-4.08 (2H,m), 7.46 (4H,s).

b) p-Trimethylgermylacetophenone

A solution of 420 mg (1.5 mmol) of2-(4-trimethylgermylphenyl)-2-methyl-1,3-dioxolane and 56 mg (0.19 mmol)of pyridinium p-toluenesulfonate (PPTS) in 1.35 g (62.5 mmol) of waterand 10 ml of acetone was refluxed for 2 hours and stirred at roomtemperature for 1.5 days. The reaction mixture was extracted withpetroleum ether. The extract was washed successively with 2Nhydrochloric acid, water and sat.aq.NaHCO₃, dried and evaporated.

The residue was purified by column chromatography on silica gel [eluent:methylene chloride-n-hexane (2:3)] to give 344 mg of colorless liquid.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.41 (9H,s), 2.60 (3H,s), 7.58 (2H,d,J=8.3Hz), 7.91 (2H,d,J=8.3 Hz).

REFERENCE 2 m-Trimethylsilylaniline

a) 1-Nitro-3-trimethylsilylbenzene

To a solution of 1.50 g (6.75 mmol) of m-bis(trimethylsilyl)benzene in4.0 ml of acetic anhydride was added dropwise a solution of 1.6 ml (35.6mmol) of 94% nitric acid in 5 ml of acetic anhydride at 130° C. withstirring. The mixture was stirred for 30 minutes. The reaction mixturewas poured into a mixture of ice and 2% potassium carbonate solution andmethylene chloride and separated. The aqueaus layer was extracted withmethylene chloride. The organic layer was washed successively with waterand 2% potassium hydroxide solution, dried and evaporated. The residuewas purified by column chromatogaphy on silica gel [eluent: methylenechloride-cyclohexane (1:3-1:5)] to give 475 mg of pale yellow liquid.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.35 (9H,s), 7.50 (1H,t,J=8 Hz), 7.81(1H,d,J=8 Hz), 8.15 (1H,d,J=8 Hz), 8.32 (1H,s).

b) m-Trimethylsilylaniline

m-Nitrotrimethylsilylbenzene (200 mg) was catalytically hydrogenatedover Pd-C in 7.5 ml of benzene at atmospheric pressure for 40 minutes.The catalyst was filtered off and washed with benzene and dry MeOH,successively. The filtrate and washings were mixed and evaporated. Theresidue was purified by column chromatography on silica gel [eluent:methylene chloride] to give 169 mg of pale brown liquid.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.26 (9H,s), 3.61 (2H,s), 6.6-7.0 (3H,m),7.16 (1H,t,J=8 Hz).

EXAMPLE 1 4-(3-Trimethylsilylphenylcarbamoyl)benzoic Acid

a) Methyl 4-(3-Trimethylsilylphenylcarbamoyl)benzoate

To a solution of 135 mg (0.817 mmol) of m-trimethylsilylaniline in 8 mlof dry benzene were added 1.0 ml of dry pyridine and 179 mg (0.900 mmol)of methyl p-chloroformylbenzoate, successively. The mixture was stirredat room temperature for 20 hours. To the reaction mixture was addedwater and the aqueous solution was extracted with AcOEt. The extract waswashed successively with water, sat.eq.NaHCO₃ and sat.aq.NaCl, dried andevaporated to give 272 mg of white powder, which was purified by columnchlomatography on silica gel (eluent: methylene chloride) to give 266 mgof white powder (yield: 99%). Recrystallization of the powder from amixture of methylene chloride, n-hexane and chloroform gave 120 mg ofwhite needles, m.p.125-126° C. (yield 45%).

MS spectrum m/z: 327(M⁺), 312(M⁺ -15)

¹ H-NMR spectrum δ(CDCl )ppm: 0.28 (9H,s), 3.96 (3H,s), 7.3-7.8 (5H,m),7.98 (2H,d,J=8 Hz), 8.13 (2H,d,J=8 Hz).

b) 4-(3-Trimethylsilylphenylcarbamoyl)benzoic Acid

To a solution of 82 mg (0.25 mmol) of methyl4-(3-trimethyl-silylphenylcarbamoyl)benzoate in 2 ml of EtOH was added 1ml (2 mmol) of 2N sodium hydroxide solution and the mixture was stirredat room temperature for 4 hours. The reaction mixture was neutralizedwith 1N hydrochloric acid and extracted with AcOEt. The extract waswashed sucessively with hydrochloric acid and sat.aq.NaCl, dried andevaporated. The residue was recrystallized from MeOH to give 48 mg ofwhite prisms, m.p.211-213° C. (yield 61%).

MS spectrum m/z: 313(M⁺), 298(M⁺ -15), 149(0⁺ ═C-C₆ H₄ --COOH).

IR spectrum νcm⁻¹ : 1694, 1669.

¹ H-NMR spectrum δ(CDCl₃ -DMSO-d₆)ppm: 0.29 (9H,s), 7.3-7.8 (4H,m), 8.05(2H,d,J=8 Hz), 8.13 (2H,d,J=8 Hz), 9.66 (1H,br).

High resolution mass spectrum for C₁₇ H₁₉ NO₃ Si: Calculated m/z:313.1133. Found m/z: 313.1164.

REFERENCE 3 3,5-Bis(trimethylsilyl)aniline

a) 1-Nitro-3,5-bis(trimethylsilyl)benzene

To a solution of 1.18 g (4.00 mmol) of sym-tris(trimethylsilyl)benzenein 1.7 ml of acetic anhydride was added a solution of 0.4 ml (9.1 mmol)of 94% nitric acid in 1.7 ml of acetic anhydride at -10° C. The mixturewas stirred at 10 to -5° C. for 2 hours and then at room temperature for22 hours. The reaction mixture was poured into sodium hydroxide solutionand the aqueous solution was extracted with methylene chloride. Theextract was evaporated. The residue was purified by columnchromatography on silica gel [eluent: petroleum ether] to give 636 mg ofpale yellow crystals, m.p.86°-87° C. (yield 59%).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.33 (18H,s), 7.90 (1H,t,J=1.1 Hz), 8.29(2H,d,J=1.1 Hz).

b) 3,5-Bis(trimethylsilyl)aniline

1-Nitro-3,5-bis(trimethylsilyl)benzene (264 mg, 0.99 mmol) wascatalytically hydrogenated over 10% Pd-C in 15 ml of benzene atatmospheric pressure for 135 minutes. The catalyst was filtered off andwashed with benzene. The filtrate and washings were mixed andevaporated. The residue was purified by column chromatography on silicagel [eluent: methylene chloride-n-hexane (2:1)] to give 224 mg of lighttan-colored low melting solid (yield 96%).

¹ H-NMR spectrum δ(CDCl )ppm: 0.24 (18H,s), 3.36 (2H,brs), 6.84(2H,brs), 7.07 (1H,brs).

EXAMPLE 2 4-(3,5-Trimethylsilylphenylcarbamoyl)benzoic Acid

a) Methyl 4-(3,5-Trimethylsilylphenylcarbamoyl)benzoate

To a solution of 220 mg (0.93 mmol) of 3,5-bis(trimethylsilyl)anilineand 187 mg (0.94 mmol) of methyl p-chloroformylbenzoate in 10 ml of drybenzene was added 1 ml of dry pyridine. The mixture was stirred for 5.75hours. Water was added to the reaction mixture and the aqueous layer wasextracted with AcOEt. The extract was washed with 0.2M aqueous coppernitrate solution, water and sat.aq.NaHCO₃, successively, dried andevaporated. The residue was recrystallized from a mixture of methylenechloride and n-hexane to give 352 mg of white prisms, m.p.212.5°-213.5°C. (yield 95%).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.30 (18H,s), 3.97 (3H,s), 7.46(1H,t,J=1.1 Hz), 7.76 (2H,d,J=1.1 Hz), 7.79 (1H,brs), 7.96 (2H,d,J=8.4Hz), 8.17 (2H,d,J=8.4 Hz).

b) 4-(3,5-Trimethylsilylphenylcarbamoyl)benzoic Acid

To a solution of 300 mg (0.75 mmol) of methyl4-(3,5-trimethylsilylphenylcarbamoyl)benzoate in 5 ml of EtOH was added3 ml of 2N sodium hydroxide solution and the mixture was stirred at roomtemperature overnight. The pH of the reaction mixture was adjusted to3.0 with 2N hydrochloric acid. The aqueous solution was extracted withAcOEt. The extract was dried and evaporated. The white residue wasrecrystalized from a mixture of AcOEt and cyclohexane and washed withn-hexane to give 255 mg of white needles, m.p. 252°-253.5° C. (yield88%).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.30 (18H,s), 7.46 (1H,t,J=1.1 Hz), 7.77(2H,brs), 7.80 (1H,brs), 7.99 (2H,d,J=8.1 Hz), 8.21 (2H,d,J=8.1 Hz)

High resolution mass spectrum for C₂₀ H₂₇ NO₃ Si₂ : Calculated m/z :385.1528. Found m/z : 385.1505.

REFERENCE 4 3,5-Bis(trimethylsilyl)benzoic Acid

A suspension of 2.0 g (14 mmol) of Ca(0Cl)2, 1.38 g(10 mmol) ofpotassium carbonate and 0.40 g (7.12 mmol) of potassium hydroxide in 40ml of water was stirred at 65° C. for 30 minutes and filtered. Thefiltrate was added to 0.53 g (2 mmol) of3',5'-bis(trimethylsilyl)acetophenone and the mixture was refluxed for7.5 hours with stirring. After cooling, 3 ml of aqueous sodium bisulfitesolution was added to the reaction mixture. The aqueous solution wasextracted with AcOEt. The extract was washed successively with water andsat.aq.NaCl, dried over anhyd.Na₂ SO₄ and evaporated. The residue waspurified by column chromatography on silica gel [eluent: n-hexane-AcOEt(2:1-1:1)] to give 0.27 g of white powder, m.p.>300° C. (yield 51%).

MS spectrum m/z: 266 (M⁺).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.32 (18H,s), 7.88 (1H,t,J=1.1 Hz), 8.24(2H,d,J=1.1 Hz).

EXAMPLE 3 4-[3,5-Bis(trimethylsilyl)phenylcarboxamido]benzoic Acid

a) Methyl 4-[3,5-Bis(trimethylsilyl)phenylcarboxamido]benzoate

To a suspension of 1.064 g (4 mmol) of 3,5-bis(trimethylsilyl)benzoicacid and 1.05 g of potassium carbonate in 104 ml of dry benzene wereadded 0.64 ml (8.8 mmol) of thionyl chloride and 0.34 ml (4.4 mmol) ofN,N-dimethylformamide (DMF) at room temperature with stirring. Themixture was stirred at room temperature for 3 hours and the insolublesubstance was filtered off. The filtrate was evaporated and the residuewas dissolved in 25 ml of dry tetrahydrofuran. To the solution wereadded 1.23 ml (8.8 mmol) of triethylamine and 0.665 g (4.4 mmol) ofmethyl p-aminobenzoate and the mixture was stirred at room temperatureovernight. The reaction mixture was made weakly acid with 0.5Nhydrochloric acid and extracted with methylene chloride.

The extract was successively washed with water and sat.aq.NaCl, driedover anhyd.Na₂ SO₄ and evaporated. The residue was purified by columnchromatography on silica gel (eluent: n-hexane-AcOEt (5:1)) to give 1.34g of pale yellow crystals, m.p.191°-192° C. (yield 84%).

MS spectrum m/z: 399 (M⁺)

¹ H-NMR spectrum δ(CDCl₃) ppm: 0.31 (18H,s), 3.90 (3H,s), 7.74(2H,d,J=8.8 Hz), 7.83 (1 H,t,J=1.1 Hz), 7.96 (2H,d,J=1.1 Hz), 8.04(2H,d,J=8.8 Hz), 8.14 (1H, br.s).

b) 4-[3,5-Bis(trimethylsilyl)phenylcarboxamido]benzoic Acid

To a solution of 22 mg(0.055 mmol) of methyl4-[3,5-bis(trimethylsilyl)phenylcarboxamido]benzoate in 6 ml of EtOH wasadded 3 ml of 2N aqueous sodium hydroxide solution and the mixture wasstirred at room temperature overnight. The reaction mixture was madeweakly acid with hydrochloric acid and extracted with AcOEt. The extractwas washed with sat.aq.NaCl, dried over MgSO₄ and evaporated. Theresidue was recrystallized from a mixture of AcOEt and n-hexane to give14 mg of colorless prisms, m.p.276°-280° C. (dec.) (yield 66%).

MS spectrum m/z : 385 (M⁺)

¹ H-NMR spectrum δ(CDCl₃) ppm: 0.33 (18H,s), 7.78 (2H,d,J=8.8 Hz), 7.84(1H,br.s), 7.94 (2H,d,J=0.9 Hz), 8.14 (2H,d,J=8.8 Hz).

EXAMPLE 4 Methyl 4-[3,5-Bis(trimethylsilyl)phenylcarboxy]benzoate

To a suspension of 665 mg (2.5 mmol) of 3,5-bis(trimethylsilyl)bonzoicacid and 670 mg of potassium carbonate in dry benzene were added 0.40 ml(5.5 mmol) of thionyl chloride and 0.21 ml (2.75 mmol) ofN,N-dimethylformamide at room temperature with stirring. The mixture wasstirred at room temperature for 3 hours. The insoluble matter wasfiltered off and the filtrate was evaporated. The residue was dissolvedin 17.5 ml of dry tetrahydrofuran and 0.77 ml(5.5 mmol), oftriethylamine and 418 mg (2.75 mmol) of methyl p-hydroxybenzoate wereadded to the solution. The mixture was stirred at room temperature for 1day. The reaction mixture was made weakly acid with hydrochloric acidand extracted with methylene chloride. The extract was successivelywashed with water and sat.aq.NaCl, dried over anhyd.Na₂ SO₄ andevaporated.

The residue was purified by column chromatography on silica gel[eluent:n-hexane-AcOEt (10:1)] to give 930 mg of white crystals (yield93%), which was recrystalized from an aqueous methanol to give 790 mg ofcolorless needles, m.p. 81°-82° C. (yield 79%).

MS spectrum m/z : 400(M⁺), 385(M⁺ -15)

¹ H-NMR spectrum δ(CDCl₃) ppm:0.33 (18H,s), 3.93 (3H,s), 7.30(2H,d,J=8.8 Hz), 7.91 (1H,t,J=0.9 Hz), 8.13 (2H,d,J=8.8 Hz), 8.30(1H,d,J=0.9 Hz).

EXAMPLE 5 4-[(3-Trimethylsilylphenyl)ethenyl]benzoic Acid

a) (m-Trimethylsilylbenzyl)phosphonium Bromide

A solution of 730 mg (3.00 mmol) of m-trimethylsilylbenzyl bromide and1.18 g (4.50 mmol) of triphenylphosphine in 10 ml of dry toluene wasrefluxed for 4.5hours in an atmosphere of argon (125°-135° C. by oilbath). The precipitate was collected by filtration, and washed withtoluene to give 1.361 g of white crystals, which were dried in vacuo(yield 90%).

¹ H-NMR spectrum δ(CD30D)ppm: 0.30 (9H,S), 5.13 (2H,d,J=16 Hz), 7.1-8.1(19H,m).

b) Methyl 4-[(3-Trimethylsilylphenyl)ethenyl]benzoate

(m-Trimethylsilylbenzyl)phosphonium bromide (758 mg, 1.50 mmol) andmethyl 4-formylbenzoate (258 mg, 1.57 mmol) were added to aNaOMe-methanol solution, which was prepared from 40 mg (1.74 mmol) of Nametal and 15 ml of dry methanol, and the mixture was stirred for 17hours. The precipitate (trans form) was collected by filtration, washedwith a cooled mixture of MeOH and n-hexane, and dried in vacuo to give115 mg of white crystals. The mother liquors were evaporated anddissolved in CH₂ Cl₂. The insoluble substance was filtered off and thefiltrate was evaporated. The residue was purified by columnchromatography to give 60 mg of colorless oil (cis form, yield 13%), 158mg of white crystals (trans form, total yield 59%) and 110 mg ofinterfraction (yield 23%).

The trans form was recrystallized from a mixture of CH₂ Cl₂ and n-hexaneto give 149 mg of white needles. The mother liquors were evaporated. Theresidue was recrystallized from n-hexane to give 120 mg of white needles(total 269 mg, yield 58%).

m.p.113°-114.5° C.

¹ H-NMR spectrum δ(CDCl )ppm: 0.30 (9H,s), 3.92 (3H,m), 7.0-7.6 (8H,m),8.02 (2H,d,J=8 Hz).

Mass spectrum m/z: 310 (M⁺), 295 (M⁺ -15).

IR spectrum νcm⁻¹ : 1723, 1282, 1250.

UV spectrum .sub.λmax nm(logε): 323 (4.91), 232 (4.61), 209 (4.75).

The physical properties of the cis form were as follows.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.16 (9H,s), 3.90 (3H,s), 6.59 (1H,d,J=12Hz), 6.69 (1H,d,J=12 Hz), 7.1-7.4 (6H,m), 7.87 (2H,d,J=8 Hz).

IR spectrum νcm⁻¹ : 1724, 1280, 1250.

UV spectrum .sub.λmax nm(logε): 303 (3.97), 237 (4.19), 203 (4.24).

(c) 4-[(3-Trimethylsilylphenyl)ethenyl]benzoic Acid

A solution of 1.8 ml(3.6 mmol) of 2N-KOH was added to a solution of 143mg (0.461 mmol) of trans-methyl4-[(3-trimethylsilylphenyl)ethenyl]benzoate in 3 ml of EtOH. The mixturewas stirred at room temperature. The reaction mixture was adjusted toacid pH with 2N hydrochloric acid, and then the aqueous solution wasextracted with AcOEt. The extract was dried and evaporated to give 137mg of the title compound as white crystals (yield 100%), which wererecrystallized from a mixture of ethyl acetate, methylene chloride andn-hexane, and dried to give 116 mg of white crystals, m.p.216°-218° C.(yield 85%).

¹ H-NMR spectrum δ(CDCl₃ -DMSO-d₆)ppm: 0.30 (9H,s), 7.12 (1H,d,J=18 Hz),7.25 (1H,d,J=18 Hz), 7.4-7.8 (6H,m), 7.95 (2H,d,J=8 Hz).

IR spectrum νcm⁻¹ : 1670.

High resolution mass spectrum for C₁₈ H₂₀ O₂ Si: Calculated m/z:296.1232. Found m/z: 296.1250.

EXAMPLE 6 4-[3-(3-Trimethylsilylphenyl)-3-oxo-1-propenyl]benzoic Acid

To a solution of 130 mg (0.676 mmol) of 3'-trimethylsilylacetophenoneand 127 mg (0.774 mmol) of methyl 4-formylbenzoate in 4.5 ml oftetrahydrofuran(THF) were added 128 mg (3.20 mmol) of NaOH and 3 ml ofhot water, and the mixture was stirred at room temperature overnight.The reaction mixture was adjusted with 7 ml of 0.5N-HCl to pH6, and thenthe aqueous solution was extracted with ethyl acetate. The extract waswashed with 0.05N-HCl and H₂ O, dried and evaporated. The residue waspurified by column chromatography affording 133 mg of pale yellow powder(yield 61%), which was recrystallized from a mixture of methylenechloride, methanol and n-hexane to give 98 mg of pale yellow needles,m.p.179°-180° C. (yield 45%).

¹ H-NMR spectrum δ(CDCl₃)ppm1 : 0.33 (9H,s), 7.51 (1H,t,J=7.7 Hz), 7.62(1H,d,J=15.8 Hz), 7.74 (2H,d,J=8.1 Hz), 7.76 (1H,d,J=7.7 Hz), 7.82(1H,d,J=15.8 Hz), 7.99 (1H,d,J=7.7 Hz), 8.14 (2H,d,J=8.1 Hz), 8.15(1H,m).

EXAMPLE 7 4-[3-(3,5-Bistrimethysilylphenyl)-3-oxo-1-propenyl]benzoicAcid

Under ice-cooling, to a solution of 114 mg (0.43 mmol) of3',5'-bis(trimethylsilyl)acetophenone and 70 mg (0.43 mmol) of methyl4-formylbenzoate in 3 ml of THF was added a solution of 40 mg (1.00mmol) of NaOH in 2 ml of H₂ O with stirring, and the mixture was stirredin an atmosphere of prepurified argon overnight. The reaction mixturewas further added to 39 mg of NaOH, stirred for 2 days, and then thesolution was adjusted with 2N-HCl to pH≦7 and extracted with ethylacetate. The extract was dried and evaporated. The residue was purifiedby column chromatography using methylene chloride-methanol (10:1) as aneluant to give 112 mg of the desired compound (yield 66%), which wasrecrystallized from a mixture of ethyl acetate and n-hexane to give 98mg of pale yellow prisms, m.p.194°-195.5° C. (yield 57%).

¹ H-NMR spectrum δ(CDCl )ppm: 0.33 (18H,s), 7.59 (1H,d,J=15.7 Hz), 7.73(2H,d,J=8.1 Hz), 7.80 (1H,d,J=15.7 Hz), 7.87 (1H,t,J=1.1 Hz), 8.10(2H,d,J=1.1 Hz), 8.16 (2H,d,J=8.1 Hz),

High resolution mass spectrum for C₂₂ H₂₈ O₃ Si₂ : Calculated m/z:396.1575. Found m/z: 396.1558.

REFERENCE 5 3'-Trimethylgermylacetophenone

a) 2-(3-Trimethylgermylphenyl)-2-methyl-1,3-dioxolane

A mixture of 81 mg (3.33 mmol) of magnesium and 574 mg (3.75 mmol) oftrimethylgermyl chloride was stirred at 40°-50° C. in an atmosphere ofargon. To the mixture was added a solution of 729 mg (3.00 mmol) of2-(3-bromophenyl)-2-methyl-1,3-dioxolane in 10 ml of tetrahydrofuranwith stirring. The mixture was refluxed for 2.5hr. and stirred at roomtemperature overnight. To the reaction mixture was added petroleum etherand the insoluble substance was filtered off. The filtrate wasevaporated to give 874 mg of pale yellow crystals, which were purifiedby column chromatography on silica gel [eluent: methylenechloride-n-hexane (1:1)] to give 657 mg of white cubes, m.p.62.5°-63.5°C. (yield 78%).

¹ H-NMR spectrum δ(CDCl )ppm: 0.39 (9H,s), 1.67 (3H,s), 3.75-3.83(2H,m), 4.00-4.09 (2H,m), 7.33 (1H,t,J=7.4 Hz), 7.41 (1H,dt,J=7.4,1.3Hz), 7.44 (1H,ddd,J=7.4,1.9,1.3 Hz), 7.58 (1H,m).

¹³ H-NMR spectrum δ(CDCl₃)ppm: -1.76, 27.71, 64.42, 108.98, 125.24,127.66, 129.50, 132.43, 142.53, 142.56

b) 3'-Trimethylgermylacetophenone

A mixture of 351 mg (1.25 mmol) of2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane, 47 mg (0.187 mmol,0.15eq) of pyridinium p-toluenesulfonate (PPTS), 1.1126 g (62.5 mmol,50eq) of water and 10 ml of acetone was refluxed for 2.5hours. Thereaction mixture was evaporated and extracted with petroleum ether. Theextract was evaporated. The oily residue was purified by columnchromatography to give 294 mg of colorless oily substance.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.42 (9H,s), 2.62 (3H,s), 7.44(1H,ddd,J=7.7,7.3,0.6 Hz), 7.67 (1H,dt,J=7.3,1.3 Hz), 7.90(1H,ddd,J=7.7,1.9,1.3 Hz), 8.06 (1H,ddd,J=1.9,1.3,0.6 Hz)

EXAMPLE 8 4-[3-(3-Trimethylgermylphenyl)-3-oxo-1-propenyl]benzoic Acid

3'-Trimethylgermylacetophenone (49 mg,0.2 mmol) and methyl4-formylbenzoate (37 mg,0.23 mmol) was dissolved in 5 ml of a mixture of50% isopropanol and tetrahydrofuran, 1 ml of 1N aqueous potassiumhydroxide solution was added, and the mixture was stirred overnight. Thereaction mixture was adjusted to pH1 with 2N hydrochloric acid andextracted with AcOEt. The extract was evaporated and the residue waspurified by column chromatography on silica gel (eluent: MeOH-methylenechloride) and recrystallized from a mixture of AcOEt and n-hexane togive 17 mg of pale yellow prisms, m.p.186°-188° C. (yield 22%).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.45 (9H,s), 7.50 (1H,dd,J=7.9,7.3 Hz),7.62 (1H,d,J=15.8 Hz), 7.72 (1H,dt,J=7.3,1.3 Hz), 7.74 (1H,d,J=8.4 Hz),7.83 (1H,d,J=15.8 Hz),8.11 (1H,m), 8.14(1H,d,J=8.4 Hz).

REFERENCE 6 3'5'-Bis(trimethylgermyl)acetophenone

a) 2-(3,5-Bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane and2-(3-Trimethylgermyl)-2-methyl-1,3-dioxolane

To a suspension of 108 mg (4.44 mmol) of magnesium and 765 mg (5.00mmol) of trimethylgermyl chloride was added a solution of 644 mg(2.00mmol) of 2-(3,5-dibromophenyl)-2-methyl-1,3-dioxolane in 10 ml oftetrahydrofuran at 40° C., stirred in an atmosphere of argon. Themixture was stirred at 70° C. for 4.5hr. and at room temperatureovernight. The reaction mixture was poured into ice-aqueous sodiumbicarbonate solution and extracted with methylene chloride. The solventwas removed to give pale brown crystals, which were purified by columnchromatography on silica gel [eluent: methylene chloride-n-hexane (1:1)]to give 514 mg (yield 65%) of2-(3,5-bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane, m.p.54° C.,and 61 mg (yield 11%) of2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane and 75 mg of themixture, in which the ratio was 3:2 (by NMR).

The physical properties of2-(3,5-bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane were asfollows:

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.39 (18H,s), 1.68 (3H,s), 3.76-3.83(2H,m), 4.01-4.10 (2H,m), 7.50 (1H,t,J=1.1 Hz), 7.55 (2H,d,J=1.1 Hz)

The physical properties of2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane were as follows.

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.39 (9H,s), 1.67 (3H,s), 3.75-3.84(2H,m), 4.00-4.09 (2H,m), 7.33 (1H,t,J=7.3 Hz), 7.41(1H,ddd,J=7.3,1.5,1.1 Hz), 7.44 (1H,ddd,J=7.3,1.8,1.5 Hz), 7.58 (1H,m).

b)3',5'-Bis(trimethylgermyl)acetophenone

A mixture of 240 mg (0.60 mmol) of2-[3,5-bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane, 23 mg (0.090mmol) of PPTS, 10.6 ml of acetone (excess) and 540 mg (30 mmol) of waterwas refluxed for 2.5hours. The reaction mixture was evaporated andextracted with ether. The extract was evaporated to give 208 mg of paleyellow crystals, which were sublimed at 70° C., 0.5mmHg to give 189 mgof white prisms, m.p.56° C. (yield 89%).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.43 (18H,s), 2.63 (3H,s), 7.74(1H,t,J=1.1 Hz), 7.99 (2H,d,J=1.1 Hz).

IR spectrum νcm⁻¹ : 1986

EXAMPLE 9 4-[3-(3,5-Bistrimethylgermylphenyl)-3-oxo-1-propenyl]benzoicAcid

3',5'-Bis(trimethylgermyl)acetophenone 163 mg (0.46 mmol) and 96 mg(0.58 mmol) of methyl 4-formylbenzoate was dissolved in 4 ml of amixture of isopropanol and tetrahydrofuran (1:1). To the mixture wasadded 2.5 ml of 0.75N aqueous potassium hydroxide solution with stirringand the mixture was stirred at room temperature overnight. The reactionmixture was adjusted to pH3.8 with 0.2N hydrochloric acid and extractedwith AcOEt. The extract was evaporated. The residue was purified bycolumn chromatography on silicagel [eluent: methylene chloride-MeOH(10:1)] and recrystallized from a mixture of methylene chloride, MeOHand n-hexane to give 120 mg of yellow prisms, m.p.194°-195.5° C. (dec.).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.45 (18H,s), 7.59 (1H,d,J=15.8 Hz), 7.74(2H,d,J=8.3 Hz), 7.78 (1H,t,J=1.1 Hz), 7.81 (1H,d,J=15.8 Hz), 8.03(2H,d,J=1.1 Hz),8.16 (2H,d,J=8.3 Hz).

Analysis for C₂₂ H₂₈ O₃ Ge₂ : Calculated: C,54.41; H,5.81; N,0. Found:C,54.57; H,5.94; N,0.

REFERENCE 7 2'-Hydroxy-5'-trimethylsilylacetophenone

a) 2-(2-Trimethylsilyloxy-5-bromophenyl)-2-methyl-1,3-dioxolane

Under ice-cooling, to a solution of 3.11 g (12 mmol) of2-(2-hydroxy-5-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml oftetrahydrofuran was added dropwise succesively, 1.84 ml (13.2 mmol) oftriethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride withstirring. The mixture was stirred at room temperature for 2 hours andfiltered. The filtrate was concentrated under reduced pressure to give4.0 g of the crude product.

b) 2'-Hydroxy-5'-trimethylsilylacetophenone

A mixture of 321 mg (13.2 mmol) of magnesium, 0.07 ml of ethyl iodideand 1.32 ml of dry tetrahydrofuran was refluxed. After cooling, themixture was diluted with 3.96 ml of dry tetrahydrofuran and refluxed. Tothe mixture was added dropwise a solution 4.0 g of crude2-(2-trimethylsilyloxy-5-bromophenyl)-2-methyl-1,3-dioxolane, obtainedas above, in 9.6 ml of tetrahydrofuran and the reaction mixture wasrefluxed for 2 hours. After cooling, 1.68 ml (13.2 mmol) oftrimethylsilyl chloride was added and refluxed for 3 hours. Water wasadded to the reaction mixture. The mixture was extracted with ether. Theextract was washed with water and sat.aq.NaCl, dried over anhyd.Na₂ SO₄and evaporated. To the residue was added 72 ml of acetone, 10.8 ml (600mmol) of water and 0.46 g (1.8 mmol) of PPTS. The mixture was refluxedfor 3 hours and evaporated. The residue was dissolved in ether. Thesolution was washed with water, aqueous sodium bicarbonate solution andsat.aq.NaCl, dried over anhyd.Na₂ SO₄ and evaporated. The residue waspurified by column chromatography on silica gel [eluent: n-hexane-AcOEt(20:1)] to 1.66 g of pale yellow liquid (yield 67%).

MS spectrum m/z: 208(M⁺), 193(M⁺ -15).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.28 (9H,s), 2.65 (3H,s), 6.96 (1H,d,J=7.9Hz), 7.59 (1H,dd,J=7.9,1.8 Hz),7.84 (1H,d,J=1.8 Hz) 12.31 (1H,s).

EXAMPLE 104-[1-Hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1propenyl]benzoicAcid

a) 2-Acetyl-4-trimethylsilylphenyl Methyl

1,4-Benzenedicarboxylate

Under ice-cooling, to a solution of 832 mg (4 mmol) of2'-hydroxy-5'-timethylsilylacetophenone in 20 ml of tetrahydrofuran wereadded dropwise successively, 0.61 ml (4.4 mmol) of triethylamine and 874mg (4.4 mmol) of methyl p-chloroformylbenzoate with stirring. Themixture was stirred at room temperature for 1 day and filtered. Thefiltrate was evaporated and the residue was dissolved in AcOEt. Theorganic solution was washed with H₂ O, aqueous sodium bicarbonatesolution and brine, dried over anhydrous Na₂ SO₄ and evaporated. Theresidue was purified by column chromatography on silica gel [eluent:n-hexane-AcOEt (5:1)] to give 1.25 g of white crystals (yield 85%),m.p.88.5-90.5° C. .

MS spectrum m/z: 370 (M⁺).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.32 (9H,s), 2.55 (3H,s), 3.97 (3H,s),7.22 (1H,d,J=7.7 Hz), 7.73 (1H,dd,J=7.7,1.5 Hz), 7.97 (1H,d,J=1.5 Hz),8.16 (2H,d,J=8.8 Hz), 8.29 (2H,d,J=8.8 Hz).

b) Methyl4-[1-Hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoat

To a solution of 740 mg (2 mmol) of 2-acetyl-4-trimethylsilylphenylmethyl 1,4-benzenedicarboxylate in 14 ml of pyridine was added 280 mg (5mmol) of ground potassium hydroxide at room temperature with stirrig.The mixture was stirred at room temperatre overnight and poured into achilled 20%-aqueous solution of acetic acid. A deposited precipitationwas extracted with AcOEt. The extract was washed with H₂ O and saturatedaq.NaCl, dried over Na₂ SO₄ and evaporated. The residue was purified bycolumn chromatography on silica gel [eluent: n-hexane-AcOEt (5:1)] togive 200 mg of yellow crystals (yield 27%), m.p.129.5°-131° C.

MS spectrum m/z: 370 (M⁺).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.31 (9H,s), 3.96 (3H,s), 6.88 (1H,s),7.00 (1H,d,J=7.9 Hz), 7.61 (1H,dd,J=7.9,1.3 Hz), 7.85 (1H,d,J=1.3 Hz),7.97 (2H,d,J=8.8 Hz), 8.17 (2H,d,J=8.8 Hz), 12.04 (1H,s), 15.44 (1H,s).

c)4-[1-Hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1propenyl]benzoicAcid

To a solution of 148 mg (0.4 mmol) of methyl4-[1-hydroxy-3(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoate in 20 ml of ethanol was added 2 ml of 2N-sodium hydroxidesolution at room temperature with stirring. The mixture was stirred atroom temperature for 1 day and acidified with 10%-hydrochloric acid topH 4. A deposited precipilation was extracted with AcOEt. The extractwas washed with H₂ O and saturated aq.NaCl, dried over MgSO₄, andevaporated. The residue was recrystallized from methanol to give 72 mgof yellow needles (yield 51%), m.p.207°-209° C.

MS spectrum m/z: 356 (M⁺).

¹ H-NMR spectrum δ(DMSO-d₆)ppm: 0.26 (9H,s), 6.84-8.30 (8H,m).

REFERENCE 8 2'-Hydroxy-4'-trimethylsilylacetophenone

a) 2-(4-Bromo-2-trimethylsilyloxyphenyl)-2-methyl-1,3-dioxolane

Under ice-cooling, to a solutin of 3.11 g (12 mmol) of2-(2-hydroxy-4-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml oftetrahydrofuran were added dropwise successively, 1.84 ml (13.2 mmol) oftriethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride withstirring. The mixture was stirred at room temperature for 3 hours andfiltered. The filtrate was concentrated under reduced pressure to give4.0 g of the crude product.

b) 2'-Hydroxy-4'-trimethylsilylacetophenone

A mixture of 321 mg (13.2 mmol) of magnesium and 0.07 ml of methyliodide in 1.32 ml of dry tetrahydrofuran was refluxed. After cooling,the mixture was diluted with 3.96 ml of dry tetrahydrofuran. To themixture was added a solution of 4.0 g of crude2-(4-bomo-2-trimethylsilyloxyphenyl)-2-methyl-1,3-dioxolane obtainedabove in 9.6 ml of dry tetrahydrofuran dropwise under refluxing and themixture was refluxed for additional 2 hours. After cooling, 1.68 ml(13.2 mmol) of trimethylsilyl chloride was added to the reaction mixtureand the mixture was refluxed for 2 hours. After cooling, water was addedto the reaction mixture. The mixture was extracted with ether. Theorganic layer was washed with H₂ O and brine, dried over anhydrous Na₂SO₄, and evaporated. To the residue were added 72 ml of acetone, 10.8 ml(600 mmol) of water and 0.46 g (1.8 mmol) of pyridiniump-toluenesulfonate (PPTS). The mixture was refluxed for 4 hours,neutralized with aqueous sodium bicarbonate solution, and evaporated.The residue was dissolved in ether. The solution was washed with water,sodium bicarbonate and brine, dried over anhydrous Na₂ SO₄, andevaporated. The residue was purified by column chromatography on silicagel [eluent: n-hexane-AcOEt (15:1)] to give 1.08 g of pale yellow liquid(yield 43%).

MS spectrum m/z: 208 (M⁺), 198 (M⁺ -15).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.27 (9H,s), 2.63 (3H,s), 7.03(1H,dd,J=7.9,1.3 Hz), 7.14 (1H,d,J=1.3 Hz), 7.69 (1H,d,J=7.9 Hz), 12.15(1H,s).

EXAMPLE 114-[1-Hydroxy-3-(2-hydroxy-4-trimethylsilylphenyl)-3-oxo-1propenyl]benzoicAcid

a) 2-Acetyl-5-trimethylsilylphenyl Methyl

1,4-Benzenedicarboxylate

Under ice-cooling, to a solution of 832 mg (4 mmol) of2'-hydroxy-4'-timethylsilylacetophenone in 20 ml of tetrahydrofuran wereadded dropwise successively, 0.61 ml (4.4 mmol) of triethylamine and 874mg (4.4 mmol) of methyl p-chloroformylbenzoate with stirring. Themixture was stirred at room temperature for 1 day and filtered. Thefiltrate was evaporated and the residue was dissolved in AcOEt. Theorganic solution was washed with H₂ O aqueous sodium bicarbonatesolution and brine, dried over anhydrous Na₂ SO₄ and evaporated. Theresidue was purified by column chromatography on silica gel eluent:n-hexane-AcOEt (5:1)] to give 1.40 g of pale yellow viscous liquid(yield 95%).

MS spectrum m/z: 370 (M⁺).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.31 (9H,s), 2.54 (3H,s), 3.98 (3H,s),7.34 (1H,d,J=1.1 Hz), 7.51 (1H,dd,J=7.5,1.1 Hz), 7.84 (1H,d,J=7.5 Hz),8.16 (2H,d,J=9.0 Hz), 8.30 (2H,d,J=9.0 Hz).

b) Methyl4-[1-Hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoate

To a solution of 740 mg (2 mmol) of 2-acetyl-4-trimethylsilylphenylmethyl 1,4-benzenedicarboxylate in 14 ml of pyridine was added 280 mg (5mmol) of ground potassium hydroxide with stirring under ice-cooling. Themixture was stirred at same temperature for 1.5 hours and poured into achilled 20%-aqueous solution of acetic acid. A deposited precipitationwas extracted with AcOEt. The extract was washed with H₂ O and brine,dried over anhydrous Na₂ SO₄ and evaporated. The residue was purified bycolumn chromatography on silica gel [eluent: n-hexane-AcOEt (5:1)] togive 510 mg of yellow crystals (yield 69%), m.p.152°-154° C.

MS spectrum m/z: 370 (M⁺).

¹ H-NMR spectrum δ(CDCl₃)ppm: 0.29 (9H,s), 3.96 (3H,s), 6.89 (1H,s),7.06 (1H,dd,J=7.9,0.9 Hz), 7.17 (1H,d,J=0.9 Hz), 7.73 (1H,d,J=7.9 Hz),7.97 (2H,d,J=8.8 Hz), 8.15 (2H,d,J=8.8 Hz), 11.91 (1H,s), 15.41 (1H,s).

c)4-[1-Hydroxy-3-(2-hydroxy-4-trimethylsilylphenyl)-3-oxo-1propenyl]benzoicAcid

To a solution of 370 mg (1 mmol) of methyl4-[1-hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoatein 60 ml of ethanol was added 5 ml of 2N sodium hydroxide solution atroom temperature with stirring. The mixture was stirred at roomtemperature overnight, neutralized with 10% hydrochloric acid to pH 8,and evaporated H₂ O was added to the residue and the mixture wasacidified with 10%-hydrochloric acid to pH4. A deposited precipitationwas collected by filtration, dried, and recrystalized fromN,N-dimethylformamide and ethanol to give 175 mg of yellow plates (yield49%), m.p. 288°-291° C. (decomp.).

MS spectrum m/z: 356 (M⁺).

¹ H-NMR spectrum δ(DMSO-d₆)ppm: 0.27 (9H,s), 7.00-8.24 (8H,m).

It is to be understood that the invention is not to be limited to theexact details of operation, or to the exact compositions, methods,procedures, or embodiments shown and described, as modifications andequivalents will be apparent to one skilled in the art, and theinvention is therefore to be limited only by the full scope of theappended claims.

What is claimed is:
 1. A benzoic acid derivative represented by theformula (I) ##STR23## wherein R₁ represents hydrogen or lower-alkyl, R₂and R₄ represent hydrogen, or trimethylgermyl, R₃ represents hydrogen,lower-alkyl, or trimethylgermyl, R₅ represents hydrogen, lower-alkyl,acetyl or hydroxy, at least one of R₂ and R₃ being trimethylgermyl, andR₆ means hydroxy, lower-alkoxy, or a group of the formula --NR₇ R₈,wherein R₇ and R₈ mean hydrogen or lower-alkyl, and X represents a groupof the formula --NHCO-- or --COCH═CH--.
 2. A compound of claim 1 whichis 4-[3-[3,5-Bis(trimethylgermyl) phenyl]-3-oxo-1-propenyl]benzoic acid.3. A compound of claim 1 which is4-[3-(3-trimethylgermylphenyl)-3-oxo-1-propenyl]benzoic acid.
 4. Atherapeutic agent useful for treatment of psoriasis comprising as activeingredient an effective amount of a compound as claimed in claim 1, 2,or 3, together with a pharmaceutically-acceptable diluent or carrier. 5.A therapeutic agent useful for treatment of immune and inflammatorydiseases comprising as active ingredient an effective amount of acompound as claimed in claim 1, 2, or 3, together with apharmaceutically-acceptable diluent or carrier.
 6. A method ofdifferentiating neoplastic cells comprising the step of employing as theactive differentiation-inducing reagent an amount of a compound asclaimed in claim 1, 2, or 3, which is effective for such purpose.
 7. Themethod of claim 6, wherein the neoplastic cells are leukemia cells.